Process for producing 16-substituted prostaglandin es.

ABSTRACT

A novel process for manufacturing 16-substituted Δ 7  -prostaglandin Es, which include compounds expressed by the following formula (I), their enanantiomers, or their mixtures of arbitray mixing ratio, ##STR1## wherein R 1  indicates COOR 2 , CH 2  OR 3 , in which R 2  indicates a hydrogen atom, a dubstituted or unsubstituted C 1  -C 10  alkyl group, a substituted or unsubstituted C 3  -C 10  cycloalkyl group, or a substituted or unsubstituted phenyl group, and R 3  indicates a hydrogen atom, a tri(C 1  -C 7 ) hydrocarbon silyl group, a group which forms an acetal bond together with the oxygen atom of a hydroxyl group, or a C 2  -C 7  acyl group; R 4  and R 5  are identical or different, each representing a hydrogen atom, a tri(C 1  -C 7  ) hydrocarbon silyl group, or a group which forms an acetal bond together with the oxygen atom of a hydroxyl group; R 6  indicates a hydrogen atom, a C 1  -C 4  alkyl group, or a vinyl group; R 7  indicates a linear or branched C 3  -C 8  alkyl group, an alkyenyl group, or an alkynyl group, which may contain an oxygen atom; a phenyl group, a phenoxy group, or a C 3  -C 10   cycloalkyl group, which may be substituted; or a linear or branched C 1  -C 5  alkyl group which is substituted by a C 1  -C 6  alkoxy group, a phenyl group a phenoxy group, or a C 3  -C 10  cycloalkyl group, which may be substituted; and Y indicates CH 2  X or XCH 2 , in which X represents an ethylene group, a cis -or trans-vinylene group, or an ethynylene group.

FIELD OF THE INVENTION

The present invention relates to a novel process for producing16-substituted prostaglandin Es. More particularly, this inventionrelates to a novel process for producing 16-substituted prostaglandin Escomprising allowing 4-substituted-2-cyclopentenones to react with anorganocopper compound by means of conjugate addition to produce enolateintermediates, which intermediates are then allowed to react withaldehydes to give 7-hydroxy-16-substituted prostaglandin Es, which arethereafter converted into 7-organic sulfonyloxy-16-substitutedprostaglandin Es and further into 16-substituted Δ⁷ -prostaglandin Esand finally into originally desired 16-substituted prostaglandin Es.

BACKGROUND OF THE ART

Naturally occurring prostaglandins (abbreviated to PG) are known aslocal hormones (autacoid) which have high activities from the viewpointsof biology and pharmacology. Researches have, therefore, been made todevelop medicines of a new type along the lines of not only naturallyoccurring PG but also their derivatives of various kinds by skillfullytaking advantage of the physiological characteristic features of PGs.

Of the natural PGs, PGEs are the earliest known compounds, and PGE₂ hasalready been made into a drug to be used as an oxytocics because of itscontractility on the smooth muscle of the uterus and PGE₁ is used as atherapeutic drug for peripheral circulatory disorders because of itsphysiological activities such as suppressive effect against the plateletaggregation and antihypertensive action.

With regard to the production of these PGEs, many processes havehitherto been developed and reported, and the following will bementioned as epochal ones to represent these processes.

(i) A process for biosynthetically producing PGE from arachidonic acidor dihomo-γ-linolenic acid (see B. Samuelsson et al., Angew. Chem. Int.Ed. Engl., 4, 410 (1965)).

(ii) A process for obtaining PGE through an important intermediate Coreylactone (see E. J. Corey et al., J. Am. Chem. Soc., 92, 397 (1970)).

(iii) A process for producing PGE through an important intermediate2-substituted-2-cyclopentenone compound (see C. J. Sih et al., J. Am.Chem. Soc., 97, 865 (1975)).

(iv) A process wherein 5,6-dehydro PGE₂ or PGF₂ α is selectively reduced(see E. S. Ferdinandi et al., Can. J. Chem., 49, 1070 (1971); C. H. Linet al., Prostaglandin, 11, 377 (1976)).

Of these methods mentioned above, the process for obtaining PGE by thebiosynthetic method involves problems of difficulty in obtaining thematerial poly-unsaturated fatty acid, very low yield from the material,and difficult isolation and purification from the by-product. While theprocess carried out according to chemical synthesis requires many stepsof procedure before the starting material is obtained, and even when thestarting material is made readily available, the process from thestarting material to prostaglandin still includes many steps ofprocedure, thus lowering the total yield remarkably.

A report has been made with regard to a chemically synthetic process forproducing PGEs based on the improvements made upon the aforementionedprocesses, including (i) the use of starting materials which are readilyobtainable; (ii) the reaction process is short; and (iii) the totalyield is high. The intended PGEs are produced by selectively removingthe hydroxy group at the 7-position from 7-hydroxy PGEs, which have beenobtained in high yield from protected 4-hydroxy-2-cyclopentenone in asingle stage reaction, followed by the conversion of the functionalgroup if necessary (see Noyori et al., Tetrahedron Letters, 23, 4057(1982) and Tetrahedron Letters, 23, 5563 (1982)).

In parallel with the research and development of processes suited forpractical use in synthesizing prostaglandin skeletons, many reports havealso been made about the progress of researches conducted on the newapplications of synthetic prostaglandins to medicaments and a number ofresultant medical preparations based on the synthesized prostaglandinanalogues. There is accordingly a strong demand for the development ofmore efficient and practical methods for the synthesis of skeletons ofprostaglandin derivatives which are now very useful as medicaments.

DISCLOSURE OF THE INVENTION

Paying active attention to the aforementioned background of the priorart, the present inventors have made an exhaustive study of the processfor deriving the desired PGEs from the key compounds of7-hydroxy-16-substituted prostaglandin Es which can be obtained bysubjecting 16-substituted prostaglandin Es to the three-componentcoupling reaction in which the aforementioned aldehyde is used as anenolate trapping agent and have succeeded in the development of anefficient process for producing 16-substituted prostaglandin Es whichare useful as medicine, thus achieving the present invention.

The present invention relates to a process for producing 16-substitutedprostaglandin Es, which include compounds expressed by the followingformula (I), or their enantiomers, or their mixtures of arbitrary mixingratio, ##STR2## wherein R¹ indicates COOR², CH₂ OR³, or COCH₂ OR³, inwhich R² indicates a hydrogen atom, a substituted or unsubstituted C₁-C₁₀ alkyl group, a substituted or unsubstituted C₃ -C₁₀ cycloalkylgroup, or a substituted or unsubstituted phenyl group, and R³ indicatesa hydrogen atom, a tri (C₁ -C₇) hydrocarbon silyl group, a group whichforms an acetal bond together with the oxygen atom of a hydroxyl group,or a C₂ -C₇ acyl group; R⁴ and R⁵ are identical or different, eachrepresenting a hydrogen atom, a tri (C₁ -C₇) hydrocarbon silyl group, ora group which forms an acetal bond together with the oxygen atom of ahydroxyl group; R⁶ indicates a hydrogen atom, a C₁ -C₄ alkyl group, or avinyl group; R⁷ indicates a linear or branched C₃ -C₈ alkyl group, analkenyl group, or an alkynyl group, which may contain an oxygen atom; aphenyl group, a phenoxy group, or a C₃ -C₁₀ cycloalkyl group, which maybe substituted; or a linear or branched C₁ -C₅ alkyl group which issubstituted by a C₁ -C₆ alkoxy group, a phenyl group, a phenoxy group,or a C₃ -C₁₀ cycloalkyl group, which may be substituted; and Y indicatesCH₂ X or XCH₂, in which X represents an ethylene group, a cis- ortrans-vinylene group, or an ethynylene group, which process comprisesmaking 7-hydroxy-16-substituted prostaglandin Es, which includecompounds expressed by the following formula (IV'), their enantiomers,or their mixtures of arbitrary mixing ratio, ##STR3## wherein R¹¹indicates COOR²¹, CH₂ OR³¹, or COCH₂ OR³¹, in which R²¹ represents asubstituted or unsubstituted C₁ -C₁₀ alkyl group, a substituted orunsubstituted C₃ -C₁₀ cycloalkyl group, or a substituted orunsubstituted phenyl group, and R³¹ represents a tri (C₁ -C₇)hydrocarbon silyl group, a group which forms an acetal bond togetherwith the oxygen atom of a hydroxyl group, or a C₂ -C₇ acyl group; R⁴¹and R⁵¹ are identical or different, each representing a tri (C₁ -C₇)hydrocarbon silyl group, or a group which forms an acetal bond togetherwith the oxygen atom of a hydroxyl group; R⁶, R⁷, and Y are as definedhereinbefore, to react with an organic sulfonic acid halide or anhydridein the presence of a basic compound to produce 7-organicsulfonyloxy-16-substituted prostaglandin Es, which include compoundsexpressed by the following formula (III'), their enantiomers, or theirmixtures of arbitrary mixing ratio, ##STR4## wherein R⁸ indicates a C₁-C₄ alkyl group or a phenyl group which may be substituted; R¹¹, R⁴¹,R⁵¹, R⁶, R⁷, and Y are as defined hereinbefore, which are furthertreated with a basic compound, followed by the deprotecting reactionand/or the hydrolytic reaction, if necessary, to give 16-substituted Δ⁷-prostaglandin Es, which include compounds expressed by the followingformula (II), their enantiomers, or their mixtures of arbitrary mixingratio, ##STR5## wherein R¹, R⁴, R⁵, R⁶, R⁷ and Y are as definedhereinbefore, and lastly selectively reducing the double bonds at the 7-and 8-positions, followed by the deprotecting reaction and/or thehydrolytic reaction, if necessary.

The 7-hydroxy-16-substituted prostaglandin Es of formula (IV'), whichare the material compounds in the process for producing 16-substitutedPGEs of the present invention, are produced as follows.

A 4-substituted-2-cyclopentenone (hereinafter referred to as a compoundexpressed by formula (VI')) represented by the following formula (VI')##STR6## wherein R⁴¹ is as defined hereinbefore, is made to undergo theconjugate addition in the presence of a trivalent organic phosphoruscompound with an organocopper compound, which is obtained from anorganic lithium compound expressed by the following formula (VII')##STR7## wherein R⁵¹, R⁶ and R⁷ are as defined hereinbefore, and acopper compound expressed by the following formula (VIII)

    CuQ                                                        (VIII)

wherein Q indicates a halogen atom, a cyano group, a phenylthio group,or a 1-pentynyl group, by the reaction carried out in an aprotic inertorganic solvent, and then making the conjugate addition adduct reactwith an aldehyde expressed by the following formula (IX') ##STR8##wherein R¹¹ and Y are as defined hereinbefore, to give the desiredcompound of formula (IV').

The abovementioned 4-substituted-2-cyclopentenone compounds expressed byformula (VI'), both their racemic form and optically active compounds,are all known compounds and can be easily obtained (Org. Syn. Chem.,vol. 41, No. 10, pg. 896-903 (1983)). R⁴¹ in the aforementioned formula(VI') and R⁵¹ in the aforementioned formula (VII') are bothhydroxyl-protecting groups and are identical or different, eachrepresenting a tri(C₁ -C₇) hydrocarbon silyl group, or a group whichforms an acetal bond together with the oxygen atom of a hydroxyl group.As the tri(C₁ -C₇) hydrocarbon silyl group, such tri(C₁ -C₄) alkylsilylgroups as a trimethylsilyl group, triethylsilyl group, andt-butyldimethylsilyl group, and such diphenyl(C₁ -C₄) alkyl groups as at-butyldiphenyl-silyl group, and such phenyldi(C₁ -C₄) alkyl groups as aphenyldimethylsilyl group or a tribenzylsilyl group may be mentioned. Asthe groups which form an acetal bond together with the oxygen atom of ahydroxyl group, a methoxymethyl group, 1-ethoxyethyl group,2-methoxy-2-propyl group, 2-ethoxy-2propyl group, (2-methoxyethoxy)methyl group, benzyloxy methyl group, 2-tetrahydrofuranyl, and6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]-4-hexyl group, for instance, maybe mentioned. Of these groups mentioned above, a trimethylsilyl group,t-butyldimethylsilyl group, diphenyl-t-butylsilyl group,2-tetrahydrofuranyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group,(2-methoxyethoxy) methyl group, and6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]-4-hexyl group may be mentioned asdesirable ones for R⁴¹ and R⁵¹.

R⁶ in the abovementioned formula (VII') indicates a hydrogen atom, C₁-C₄ alkyl group such as a methyl group, ethyl group, and butyl group,and a vinyl group, of which, a hydrogen atom, methyl group, and vinylgroup may be mentioned as the desirable ones. R⁷ indicates a linear orbranched C₃ -C₈ alkyl group, an alkenyl group, an alkynyl group, whichmay contain an oxygen atom; a phenyl group, a phenoxy group, a C₃ -C₁₀cycloalkyl group, which may be substituted; or a linear or branched C₁-C₅ alkyl group which is substituted by a C₁ -C₈ alkoxy group, a phenylgroup, a phenoxy group, a C₃ -C₁₀ cycloalkyl group, which may besubstituted. As the linear or branched C₃ -C₈ alkyl group, alkenylgroup, or alkynyl group, which may contain an oxygen atom; a2-methoxyethyl group, 2-ethoxyethyl group, propyl group, butyl group,pentyl group, hexyl group, heptyl group, octyl group, 1-methyl-1-buthylgroup, 2-methylhexyl group, 2-methyl-2-hexyl group, 2-hexyl group,1,1-dimethylpentyl group, 1,5-dimethyl-4-hexenyl group, 1-butenyl group,1-butynyl group, 2-butenyl group, and 2-butynyl group may be mentioned.Of these, a propyl group, butyl group, pentyl group, 1-methyl-1-butylgroup, 2-methyl-1-butyl group, 1-butenyl group, 1-butynyl group,2-butenyl group, and 2-butynyl group are preferable ones and a butylgroup may be mentioned as an especially preferable one. As substituentof the phenyl group, phenoxy group, or C₃ -C₁₀ cycloalkyl, which may besubstituted; a halogen atom, hydroxy group, C₂ -C₇ acyloxy group, C₁ -C₄alkyl group which may be substituted by a halogen atom, C₁ -C₄ alkoxygroup which may be substituted by a halogen atom, nitrile group,carboxyl group and (C₁ -C₆) alkoxycarbonyl group are desirable ones. Asthe halogen atom, a fluorine atom, chlorine atom, and bromine atom maybe mentioned and a fluorine atom and chlorine atom, are desirable. Asthe C₂ -C₇ acyloxy group, an acetoxy group, propionyloxy group,n-butyryloxy group, isobutyryloxy group, n-valeryloxy group,isovaleryloxy group, caproyloxy group, enanthoyloxy group and benzoyloxygroup may be mentioned.

As the C₁ -C₄ alkyl group which may be substituted by a halogen atom, amethyl group, ethyl group, n-propyl group, isopropyl group, n-butylgroup, chloromethyl group, dichloromethyl group, and trifluoromethylgroup may be mentioned as preferable ones. As the C₁ -C₄ alkoxy groupwhich may be substituted by a halogen atom, a methoxy group, ethoxygroup, n-propoxy group, isopropoxy group, n-butoxy group, chloromethoxygroup, dichloromethoxy group and trifluoromethoxy group, for instance,may be preferable ones. As the C₁ -C₆ alkoxycarbonyl group, anethoxycarbonyl group, butoxycarbonyl group, and hexyloxycarbonyl groupmay be mentioned.

A substituted phenyl group, phenoxy group, or C₃ -C₁₀ cycloalkyl groupcan have 1 to 3, preferably 1 of the aforementioned substituent groups.As the substituted or unsubstituted C₃ -C₁₀ cycloalkyl group, suchsubstituted by the same substituent groups as mentioned above orunsubstituted, saturated or unsaturated, groups of C₃ -C₁₀, preferablyC₅ -C₆, or most preferably C₆, as a cyclopropyl group, cyclopentylgroup, cyclohexyl group, cyclohexenyl group, cycloheptyl group,cyclooctyl group and cyclodecyl group, for instance, may be mentioned.

As linear or branched C₁ -C₅ alkyl group which is substituted by the C₁-C₆ alkoxy group, phenyl group, phenoxy group, a C₃ -C₁₀ cycloalkylgroup, which may be substituted, those groups which are combinations ofgroups exemplified in the respective definitions given above may bementioned as the preferable ones.

The carbon atom having substituents of R⁶ and R⁷ in the aforementionedformula (VII') is usually an asymmetric carbon atom with theconfiguration of either an R-isomer or an S-isomer and the presentinvention involves both isomers, and furthermore involves dl-isomer andmixtures containing those of R- and S-isomer in an arbitrary mixingratio.

In formula (VIII), Q indicates a halogen atom, a cyano group, aphenylthio group, or a 1-pentynyl group. As the halogen atom, a chlorineatom, bromine atom, and iodine atom may be mentioned. Of these, aniodine atom, cyano group, phenylthio group, and 1-pentynyl group arepreferable and an iodine atom and 1-pentynyl group are especiallypreferable.

In formula (IX'), R¹¹ indicates COOR²¹, CH₂ OR³¹, or COCH₂ OR³¹, inwhich R²¹ represents a substituted or unsubstituted C₁ -C₁₀ alkyl group,a substituted or unsubstituted C₃ -C₁₀ cycloalkyl group, or asubstituted or unsubstituted phenyl group, and R³¹ indicates a tri(C₁-C₇) hydrocarbon silyl group, a group which forms an acetal bondtogether with the oxygen atom of a hydroxyl group, or a C₂ -C₇ acylgroup.

As for R²¹, those groups, which may be substituted by any of thesubstituent groups mentioned as the substituent groups in theaforementioned case of R⁷, including linear or branched C₁ -C₁₀ alkylgroups such as a methyl group, ethyl group, propyl group, isopropylgroup, butyl group, sec-butyl group, isobutyl group, t-butyl group,pentyl group, hexyl group, heptyl group, octyl group, nonyl group, anddecyl group, or C₃ -C₁₀ cycloalkyl groups such as a cyclopropyl group,cyclopentyl group, cyclohexyl group, cyclooctyl group, and cyclodecylgroup, or phenyl group may be mentioned. Of these mentioned above, C₁-C₁₀ alkyl groups, especially a methyl group is preferable.

As the tri(C₁ -C₇) hydrocarbon silyl group and the group which forms anacetal bond together with the oxygen atom of a hydroxyl group which arerepresented by R³¹, these group which are cited for R⁴¹ and R⁵¹ mayagain be cited here as preferable ones, and as the C₂ -C₇ acyl groups,those substituent groups exemplified for R⁷ may be cited here again asdesirable ones.

In formula (IX'), Y indicates CH₂ X or XCH₂, in which X represents anethylene group, a cis- or trans-vinylene group, or an ethynylene group.

For obtaining an organocopper compound from an organic lithium compoundexpressed by formula (VII') and a copper compound expressed by formula(VIII), the literature, Tetrahedron; Lett., 21, 1247 (1980), may besuggested.

The reaction between 4-substituted-2-cyclopentenone expressed by formula(VI') and an organocopper compound is stoichiometrically conducted inequimolecular quantities; however, it is an ordinary practice to use 0.5to 2.0 moles, most preferably 1.1 to 1.3 moles of an organocoppercompound to 1 mole of 4-substituted-2-cyclopentenone.

The reaction temperature ranges from -120° C. to 0° C., most preferablyfrom -90° C. to -30° C. The reaction time varies depending upon thereaction temperature; however, about 1 hour is ordinarily enough whenthe reaction is conducted at -78° C. to -20° C.

The reaction is carried out in the presence of an organic solvent. Aninert aprotic organic solvent, which remains liquid at the reactiontemperature and does not react with a reaction reagent, is to be used inthe reaction.

As the inert aprotic organic solvent, such saturated hydrocarbons aspentane, hexane, and heptane; such aromatic hydrocarbons as benzene,toluene, and xylene; such etheric solvents as diethyl ether,tetrahydrofuran, dioxane, dimethyloxyethane, and diethylene glycoldimethyl ether; and ether so-called aprotic polar solvents such ashexamethylphosphonic triamide, N,N-dimethylformamide (DMAC), dimethylsulfoxide, sulfolane, and N-methylpyrrolidone may be mentioned. Thesesolvents can be used as a mixed solvent consisting of two or moresolvents. As the aprotic inert organic solvent, the inert solvent whichhas been used in preparing said organocopper lithium compound can againbe used in its entirety. This means that said4-substituted-2-cyclopentenone is added to the reaction system in whichsaid organic lithium compound has been prepared to cause the reaction.The amount of an organic solvent to be used in the reaction may be suchas amount as enough to make the reaction proceed satisfactorily. It isan ordinary practice to use a solvent 1 to 100 times by volume,preferably 2 to 30 times by volume, the material.

It is advisable to carry out the reaction in an atmosphere of nitrogenor argon gas. It is better to carry on the reaction in the presence oftrivalent phosphorus compound such as trialkylphosphine (liketriethylphosphine and tributylphosphine), trialkylphosphate (liketrimethyl phosphate, triethyl phosphate, and triisopropyl phosphate),etc. It is especially desirably to use tributylphosphine.

It is assumed in the present invention that all the operations taken upto this point have completed the formation of an enolate by conjugateaddition to introduce an alkenyl group, which forms an organic radicalof said organocopper compound, at the 3-position of the4-substituted-2-cyclopentenone and resulted in the formation of an anionat the 2-position. When this enolate formed by conjugate addition isallowed to react with aldehyde expressed by the aforementioned formula(IX'), the desired 7-hydroxy-16 substituted prostaglandin E is obtained.

The reaction with said aldehyde is carried out by adding aldehyde ofaforementioned formula (IX') which may be diluted with said aproticorganic solvent, to the reaction system in which an organocoppercompound is conjugately added to the 4-substituted-2-cyclopentenone.

The reaction of said aldehyde with an enolate which has been prepared byconjugated addition proceeds stoichiometrically in amounts equimolarwith each other; however, it is a usual practice to use 0.5 to 2.0moles, or more preferably 0.8 to 1.2 moles of aldehyde to 1 mole ofinitially used 4-substituted-2-cyclopentenone.

The reaction is conducted at a temperature ranging from -120° C. to 0°C., preferably from -90° C. to -30° C. The reaction time variesdepending upon the reaction temperature; however, the reaction isusually completed satisfactorily in about 1 hour at -78° C. to -40° C.It is efficient to determine the end point of the reaction by means ofthin-layer chromatography and the like.

After the reaction is completed, the obtained product is isolated andpurified from the reaction mixture according to the ordinarily practicedmethods such as extraction, washing, chromatography, or theircombination.

The product thus obtained has the structure represented by formula (IV')in which the respective hydroxyl groups and carboxylic acid areprotected and is used as the starting material in the succeedingprocess.

The compound of formula (IV'), upon being subjected to the deprotectingreaction and/or the hydrolytic reaction as case may require, is led to7-hydroxy-16-substituted prostaglandin Es expressed by the followingformula (IV) ##STR9## wherein R¹ indicates COOR², CH₂ OR³, or COCH₂ OR³,in which R² indicates a hydrogen atom, a substituted or unsubstituted C₁-C₁₀ alkyl group, a substituted or unsubstituted C₃ -C₁₀ cycloalkylgroup, or a substituted or unsubstituted phenyl group, and R⁵ indicatesa hydrogen atom, a tri(C₁ -C₇) hydrocarbon silyl group, a group whichforms an acetal bond together with the oxygen atom of a hydroxyl group,or a C₂ -C₇ acyl group; R⁴ and R⁵ are identical or different, eachrepresenting a hydrogen atom, a tri(C₁ -C₇) hydrocarbon silyl group, ora group which forms an acetal bond together with the oxygen atom of ahydroxyl group; R⁶ indicates a hydrogen atom, a C₁ -C₄ alkyl group, or avinyl group; R⁷ indicates a linear or branched C₃ -C₈ alkyl group, analkenyl group, or an alkynyl group, which may contain an oxygen atom; aphenyl group, a phenoxy group, or a C₃ -C₁₀ cycloalkyl group, which maybe substituted; or a linear or branched C₁ -C₅ alkyl group which issubstituted by a C₁ -C₆ alkoxy group, a phenyl group, a phenoxy group,or a C₃ -C₁₀ cycloalkyl group, which may be substituted; and Y indicatesCH₂ X or XCH₂, in which X represents an ethylene group, a cis- ortrans-vinylene group, or an ethynylene group, of which these derivativeswhose R⁴ and R⁵ are both hydrogen atoms have per se physiologicalactivities such as antiplatelet aggregation activity and anti-ulceractivity and form a group of compounds useful from the pharmaceuticalviewpoint.

The deprotecting reaction, by which the hydroxyl-protecting groups (R³¹,R⁴¹, and/or R⁵¹) in the compounds of formula (IV') are removed, iscarried out successfully by use of acetic acid, pyridiniump-toluenesulfonate, or cation-exchange resin as a catalyst, and by useof water, tetrahydrofuran, ethyl ether, dioxane, acetone, oracetonitrile as a reaction catalyst, in case where the protecting groupis a group which forms an acetal bond together with the oxygen atom of ahydroxyl group. The reaction is usually conducted at a temperatureranging from -78° C. to +30° C. for 10 minutes to 3 days. In case wherethe protecting group is a tri(C₁ -C₇) hydrocarbon silyl groups thereaction is carried out in the same solvent, at the same temperature,and for the same period of time as mentioned above, by use of aceticacid, tetrabutyl-ammonium fluoride, cesium fluoride, hydrofluoric acid,and hydrogen fluoride-pyridine as a catalyst.

The hydrolytic reaction for removing the carboxyl-protecting group (R²¹)is conducted by use of such enzymes as lipase and esterase in water orwater-containing solvent at a temperature ranging from -10° C. to +60°C. for 10 minutes to 24 hours.

In the process proposed by this invention, the 7-hydroxy-16-substitutedprostaglandin Es of formula (IV') thus obtained are then made to reactwith an organic sulfonic acid halide or anhydride in the presence of abasic compound to be led to 7-organic sulfonyloxy-16-substitutedprostaglandin Es represented by the following formula (III') (Process 1)##STR10## wherein R¹¹, R⁴¹, R⁵¹, R⁶, R⁷, R⁸, and Y are as definedhereinbefore.

As the basic compound to be used here, amines are preferable ones andamong them all, organic tertiary amines inclusive of heteroaromaticamines such as pyridine are especially preferable. As the organictertiary amines, 4-dimethylaminopyridine, triethylamine, tributylamine,diisopropylethylamine, diisopropylcyclohexylamine, andisopropyldimethylamine, for instance, may be mentioned. Of these amines,the use of 4-dimethylaminopyridine, singly or in combination with any ofother organic tertiary amines, is recommendable.

To give examples of the organic sulfonic acid halides, methanesulfonylchloride, benzenesulfonyl chloride, and p-toluenesulfonyl chloride maybe mentioned, and as the organic sulfonic acid anhydride,methanesulfonic acid anhydride may be mentioned.

The amount of organic sulfonic acid halide or anhydride to be used inthe reaction ranges from 0.5 to 10 moles, preferably from 2 to 3 molesto 1 mole of 7-hydroxy-16-substituted prostaglandin Es expressed byformula (IV'), and the amount of the basic compound ranges from 1 to 20moles, preferably from 2 to 5 moles likewise.

The reaction temperature ranges from -20° C. to 50° C., preferably from0° C. to 30° C. The completion of the reaction can be confirmed byfollowing the disappearance of the material compound on thin-layerchromatography. The reaction is usually completed in 0.5 to 10 hours. Asolvent may be used to make the reaction proceed smoothly. As thesolvent to be used in the reaction, such halogenated hydrocarbons asdichloromethane, chloroform, and 1,2-dichloroethane, such ethers asether, tetrahydrofuran, and dimethoxyethane, and such hydrocarbons asbenzene, toluene, pentane, hexane, and cyclohexane may be mentioned. Itis preferable to use dichloromethane. To mention the work-up after thereaction is over, the reaction product can be isolated and purified bysubjecting the reaction mixture to the ordinary methods (such asextraction, washing, drying, chromatography, etc.).

The 7-organic sulfonyloxy-16-substituted prostaglandin Es expressed byformula (III') is isolated. Thus obtained compounds are not only usefulas the intermediate in the succeeding stage of the present process butalso useful substances per se as novel compounds.

R⁸ in the aforementioned formula (III') represents a C₁ -C₄ alkyl groupor a phenyl groups which may be substituted. As the C₁ -C₄ alkyl group,a methyl group, ethyl group, and butyl group may be mentioned, and ofthese groups, a methyl group is especially preferable. As the phehylgroup which may be substituted, a phenyl group and p-toluyl group may bementioned as preferable groups.

The 7-organic sulfonyloxy-16-substituted prostaglandin Es represented bythe aforementioned formula (III') are then treated with a basic compoundto be led to 16-substituted Δ⁷ -prostaglandin Es expressed by theaforementioned formula (II') (Process 2).

As the basic compounds to be used here, the same basic compounds used inthe proceeding Process 1 can also be used again. More particularly, thereaction of Process 1 shows up the very initial state of the reactionand when the treatment of the reaction mixture is continued for anotherlong period of hours under the same conditions or under the raisedreaction temperature, the reaction proceeds into Process 2, where thedesulfonating reaction takes place as the secondary reaction, thusleading to the production of 16-substituted Δ⁷ -prostaglandin Esrepresented by the following formula (II') ##STR11## wherein R¹¹, R⁴¹,R⁵¹, R⁶, R⁷, and Y are as defined hereinbefore.

The 16-substituted Δ⁷ -prostaglandin Es of formula (II') obtained inProcess 1 and the succeeding work-up are further subjected to thedeprotecting reaction and/or the hydrolytic reaction, if so required, togive 16-substituted Δ⁷ -prostaglandin Es represented by the followingformula (II) ##STR12## wherein R¹, R⁴, R⁵, R⁶, R⁷, and Y are as definedhereinbefore.

The group of these compounds are useful substances not only because theyare used as the intermediates in the succeeding process but also becausethey function as the group of useful compounds which have per se theactivities including activity of suppressing the proliferation of tumorcells, anti-platalet aggregation activity, and antiulcer activity,especially in case where said compounds have hydrogen atoms for R³, R⁴and R⁵ in their structures.

The 16-substituted Δ⁷ -prostaglandin Es of formula (II) obtained inProcess 2 are then have their double bonds at the 7- and 8-positionsreduced selectively and further subjected to the deprotecting reactionand/or hydrolytic reaction, if so required, to be led to 16-substitutedprostaglandin Es, or the final products of this invention, expressed bythe following formula (I) ##STR13## wherein R¹, R⁴, R⁵, R⁶, R⁷, and Yare as defined hereinbefore.

The reaction for selectively reducing the double bonds at the 7- and8-positions can be achieved according to the following methods.

(i) The reduction reaction in which an organic tin hydride compound isused.

(ii) The reduction which is carried out by use of zincic reducing agentssuch as zinc dust, zinc-silver, and zinc-copper in the presence ofacetic acid.

(iii) The catalytic reduction conducted in the presence of the catalystfor hydrogenation such as nickel, palladium, platinum, and rhodium.

These methods are explained in detail as follows.

(i) Reduction by use of organic tin hydride:

As the organic tin hydride to the used in this reduction reaction,dibutyltin dihydride, tripropyltin hydride, triethyltin hydride,tributyltin deuteride, and triphenyltin hydride, for instance, may bementioned. Tributyltin hydride is especially preferable because of itseasy availability.

The amount of an organic tin hydride compound varies depending upon itsreactivity; however, it is a usual practice to use 1 to 1000 moles oforganic tin hydride, more preferably 1 to 100 moles, and most preferably2 to 10 moles, to 1 mole of the material compound of formula (II). Areaction solvent may be used as case may require. Benzene,tetrahydrofuran, chloroform, and dioxane are usually used; however, thereaction proceeds in the absence of a solvent and it is advisable not touse a solvent in a case where the reaction system is homogeneous.

The reaction is conducted in the presence of a reaction accelerator. Asthe reaction accelerator, such radical initiators as α,α'-azobisisobutyronitrile and di-t-butyl-peroxide, and zerovalentpalladium catalyst are used favorably.

In case where a radical initiator is used as the reaction accelerator,it is usually used in an amount of 0.001 to 10 moles to 1 mole of thestarting material of formula (II). The reaction temperature ranges from0° C. to 200° C., preferably from 30° C. to 140° C.

As the zerovalent palladium catalyst, a zerovalent palladium itself orones which form complexes with appropriate ligands may be mentioned;however, a zerovalent palladium complex which has the improvessolubility for organic substances is preferable from the viewpoint ofefficiency of a catalyst. As the ligands of such zerovalent palladiumcatalyst, 1,2-diphenylphosphine ethane, methyl-diphenylphosphine,triphenylphosphine, and dibenzylideneacetone may be mentioned, of whichtriphenylphosphine is especially preferable. As the zerovalent palladiumcomplex coordinated with such a ligand, tetrakis (triphenylphosphine)palladium (0) may be mentioned.

Also, the reaction proceeds satisfactorily even if a zerovalentpalladium catalyst is formed by reduction in the reaction system andthis may be accepted willingly in this invention.

The amount of the zerovalent palladium catalyst to be used in thereation is relative to its efficiency as a catalyst; however, it isusually enough to use it in an amount of 0.001 to 10 moles, preferably0.01 to 1 mole to 1 mole of the material compound of formula (II).

The reaction is conducted at a temperature ranging from 0° C. to 100°C., preferably from 20° C. to 60° C. The reaction is carried out in therange of 1 to 48 hours but the reaction temperature and time usuallyvaries depending upon the catalyst and reductant. The reaction can beconducted efficiently while following its process by means of gaschromatography, liquid chromatography, thin-layer chromatorgraphy.

After the reaction is over, the 16-substituted prostaglandin Esrepresented by the abovementioned formula (I) are isolated and purifiedaccording to the ordinary methods, such as by addition of water,extraction, washing, drying, separation by filtration, andconcentration, followed by separation by means of chromatography.

(ii) Reduction by use of zincic reducing agents in the presence ofacetic acid:

As the zincic reducing agents to be used in the reaction, zinc dust,zinc-silver, and zinc-copper may be mentioned. The amount of a zincicreductant to be used in the reaction is 1 to 100 moles, preferably 2 to50 moles, to 1 mole of the material compound of formula (II). A solventis used to make the reaction proceed smoothly. As the solvents, alcoholssuch as methanol, ethanol, and butanol; acetic acid, dimethyl sulfoxide,or a mixture thereof are preferably used. Of these solvents, methanol isespecially preferable.

The reaction temperature ranges from 0° C. to 120° C., preferably from10° C. to 80° C. The reaction time, which varies depending upon thereaction conditions, should preferably in the range of 1 to 48 hours,more preferably 3 to 24 hours. After the reaction is completed, thereaction mixture is subjected to ordinary aftertreatments to isolate the16-substituted prostaglandin Es expressed by the aforementioned formula(I).

(iii) Reaction by use of catalyst for hydrogenation:

As the catalysts for hydrogenation to be used in this reaction, which isconducted by used of heterogeneous catalysts for hydrogenation in theatmosphere of hydrogen, Raney nickel catalyst, palladium catalyst,platinum catalyst, and rhodium catalyst may be mentioned. The amount ofthe catalyst to be used in the reation ranges from 0.001 to 20 moles,preferably from 0.01 to 10 moles, to 1 mole of the material of formula(II).

A solvent is used to make the reaction proceed smoothly. As the solvent,such alcohols as methanol, ethanol, and butanol such ethers asdimethoxyethane, and tetrahydrofuran; dimethylformamide; or a mixedsolvent thereof are preferably used. Methanol is used most preferably.

After the reduction reaction is over, the reaction product may furtherbe subjected to the deprotecting reaction and/or hydrolytic reaction, ifnecessary.

The intermediates are thus made into the 16-substituted prostaglandin Esof formula (I), which are the final compound aimed at in the presentinvention, through Process 3.

The concrete examples of the 16-substituted prostaglandin Es expressedby formula (I) are as follows.

16-methyl-15-deoxy-16-hydroxy PGE₁

(16S)-16-methyl-15-deoxy-16-hydroxy PGE₁

(16R)-16-methyl-15-deoxy-16-hydroxy PGE₁

16-methyl-15-deoxy-16-hydroxy PGE₂

16-methyl-15-deoxy-16-hydroxy-5,6-dehydro PGE₂

16-vinyl-15-deoxy-16-hydroxy PGE₁

16-vinyl-15-deoxy-16-hydroxy PGE₂

(4Z)-15-deoxy-16-hydroxy-Δ⁴ -PGE₁

(4E)-15-deoxy-16-hydroxy-Δ⁴ -PGE₁

(16S, 4Z)-16-methyl-15-deoxy-16-hydroxy-Δ⁴ -PGE₁

(16S, 4Z)-16-methyl-15-deoxy-16-hydroxy-Δ⁴ -PGE₁

16-methyl-15-deoxy-16-hydroxy-4,4,5,5-tetradehydro PGE₁

(4Z)-16-vinyl-15-deoxy-16-hydroxy-Δ⁴ -PGE₁

(4E)-16-vinyl-15-deoxy-16-hydroxy-Δ⁴ -PGE₁

As fully described in the above, the present invention is to provide anew industrially advantageous process for producing 16-substitutedprostaglandin Es and also provide 7-hydroxy-16-substituted prostaglandinEs and 16-substituted Δ⁷ -prostaglandin Es which are importantintermediates in said process of production and also make usefulmedicines per se because of their excellent phermacological activitiessuch as anti-ulcer activity and anti-platelet aggregation activity.

BEST MODE OF CARRYING OUT THE INVENTION

The best mode of carrying out the present invention is described indetail by the following examples.

EXAMPLE 1

Synthesis of(dl)-7-hydroxy-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-PGE,methyl ester

A flask was cooled at -78° C. and 10 ml of anhydrous ethyl ether was putin the flask and then a 1.6M butyllithium solution (15 ml, 24 mM) wasadded thereto. Then, 10 ml of anhydrous ethyl ether solution of 3.91 g(11.5 mM) of (dl)-(E)-4-methyl-4-trimethylsilyloxy-1-iodo-1-octene whichwas cooled at -78° C. was added to the mixture. The reaction mixture wasstirred for 2 hours.

A homogeneous solution was separately prepared by stirring a mixture of1.57 g (12 mM) of 1-pentynylcopper (I), 6.53 ml (36 mM) ofhexamethylphosphorous triamide and 10 ml of anhydrous ethyl ether, for30 minutes. The solution was cooled to -78° C. and added to theabovementioned reaction mixture and stirred for 1 hour.

A -78° C. solution of 2.12 g (10 mM) of(dl)-4-t-butyldimethylsilyloxy-2-cyclopentenone in 20 ml of anhydrousethyl ether was added to the aforementioned reaction mixture. Themixture was stirred at -78° C. for 10 minutes and was further stirred at-40° C. for 40 minutes.

To the mixture, an ethereal solution (10 ml) of 1.90 g (12 mM) of methyl7-oxo heptanoate was added at -40° C. and the whole mixture was stirredat -40° C. for 1 hour.

The reaction mixture was poured into an aqueous acetate buffer solution(pH 4) and stirred for 15 minutes. After it was filtered through Celite,it was washed with a small amount of n-hexane, and extracted. Theseparated organic layers were collected and washed with an aqueoussolution of ammonium chloride and a saturated saline solution. Afterhaving been dried over anhydrous magnesium sulfate and concentratedunder vacuum, a crude residue was subjected to chromatography oversilica gel to give 2.94 g (yield 50%) of(dl)-7-hydroxy-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-PGE,methyl ester.

Rf=0.54 (n-hexane: ethyl acetate=2:1).

IR (KBr-disk): 3450, 1740, 1250, 840 cm⁻¹,

¹ H-NMR (CDCl₃, δ): 0-0.2 (m, 15H), 0.75 (m, 12H), 1.15-1.55 (m, 18H),2.0-2.5 (m, 8H), 3.1-3.2 (m, 1H), 3.50 (s, 3H), 3.8-4.1 (m, 1H), 5.1-5.5(m, 2H).

EXAMPLE 2 Synthesis of(dl)-7,8-dehydro-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-^(PGE)1 methyl ester

One gram of(dl)-7-hydroxy-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-PGE₁methyl ester was dissolved in 7 ml of dichloromethane and then 1.04 g of4-dimethylaminopyridine was added thereto. To the mixture, 0.29 ml ofmethanesulfonyl chloride was added at 0° C. and the resulting mixturewas stirred for 10 minutes. Thereafter the mixture was stirred at 25° C.for additional 3 hours. The reaction mixture was poured into an aqueoussolution of KHSO₄ and was extracted with dichloromethane. The separatedorganic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate, then with a saturated saline solution, and was driedover anhydrous magnesium sulfate. The concentrated reaction product wasthen subjected to column chromatography over silica gel to provide 0.65g (yield of 67%) of(dl)-7,8-dehydro-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-PGE₁methyl ester.

Rf=0.56 (n-hexane: ethyl acetate=3:1),

IR (liquid film): 1735, 1730, 1250, 840 cm⁻¹,

¹ H-NMR (CDCl₃, δ): 0-0.2 (m, 15H), 0.8 (m, 12H), 1.1-1.75 (m, 15H),2.0-2.5 (m, 8H), 3.3-3.4 (m, 1H), 3.65 (s, 3H), 4.0-4.2 (m, 1H), 5.2-5.4(m, 2H), 6.4-7.0 (m, 1H).

EXAMPLE 3 Synthesis of(dl)-15-deoxy-16-methyl-11-t-butyldimethylsilyloxy-16-trimethylsilyl-.sup.PGE1 methyl ester

One hundred and eighty milligrams of(dl)-7,8-dehydro-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-PGE₁methyl ester obtained in Example 2 was dissolved in 5 ml of isopropylalcohol and 0.4 ml of acetic acid and further 400 mg of zinc dust wereadded to the solution. The mixture was stirred at 60° C. for 1 hour.After having been cooled, the reaction mixture was filtered throughCelite, and washed with ethyl acetate. The filtrate was washed with asaturated saline solution, dried over anhydrous magnesium sulfate,filtered, concentrated in vacuo, and subjected to column chromatographyover silica gel to obtain 118 mg (yield of 66%) of(dl)-15-deoxy-16-methyl-11-t-butyldimethylsilyloxy-16-trimethylsilyl-PGE.sub.1methyl ester.

IR (liquid film): 1740.

¹ H-NMR (CDCl₃, δ): 0-1.0 (m, 15H), 0.85 (s+t, 12H), 1.15 (s, 3H),1.1-1.75 (m, 16H), 2.0-2.6 (m, 8H), 3.6 (s, 3H), 3.8-4.1 (m, 1H),5.2-5.5 (m, 2H).

Rf=0.52 (n-hexane: ethyl acetate=4:1).

EXAMPLE 4 Synthesis of(dl)-15-deoxy-16-methyl-11-t-butyldimethylsilyloxy-16-trimethylsilyl-.sup.PGE1 methyl ester

A mixture of 100 mg of(dl)-7,8-dehydro-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-PGE₁methyl ester, 200 mg of tetrakis (triphenylphosphine) palladiumcatalyst, and 0.2 ml of n-tributyltin hydride was stirred at roomtemperature for 12 hours. Thereafter, a saturated aqueous solution ofammonium chloride was added to the reaction mixture, then extracted withn-hexane, and the organic layer was washed with a saturated salinesolution. After the organic layer was dried over anhydrous magnesiumsulfate and evaporated, an obtained residue was subjected to columnchromatography over silica gel to give 55 mg (yield of 55%) of(dl)-15-deoxy-16-methy-11-t-butyldimethylsilyl-16-trimethylsilyloxy-PGE.sub.1methyl ester, the same compound as the one obtained in Example 3.

EXAMPLE 5 Synthesis of (dl)-15-deoxy-16-hydroxy-16-methyl prostaglandin^(E) 1 methyl ester

To solution of(dl)-(16RS)-11-t-butyldimethylsilyl-15-deoxy-16-methyl-16-trimethylsilyloxyprostaglandin E₁ methyl ester (537 mg, 0.95 m mol) in acetonitril (15ml) was put in a 50-ml reaction vessel, and pyridine (0.6 ml), thenhydrogen fluoride-pyridine complex (0.6 ml) were added. The mixture wasstirred at room temperature for 2.5 hours. The reaction was monitored bythin layer chromatography. After the reaction was completed, thereaction mixture was neutralized by addition of saturated aqueoussolution of sodium hydrogen-carbonate and the resulting mixture wasextracted with ethyl acetate. After the extract was washed with anaqueous solution of potassium hydrogen sulfate, with an aqueous solutionof sodium hydrogencarbonate, and with a saline solution, the separatedorganic layer was dried over anhydrous magnesium sulfate andconcentrated to leave a crude product. The crude product was subjectedto column chromatography (30 g of silica gel; hexane: ethyl acetate=1:2)to afford (dl)-15-deoxy-16-hydroxy-16-methylprostaglandin E₁ methylester (310 mg, 0.82 m mol, yield 86%).

IR (liquid film): 3410, 1740, 1160, 970, 730 cm⁻¹.

¹ H-NMR (CDCl₃, δ): 0.87 (3H, t), 1.13 (3H, s), 1.1-1.8 (16H, m),2.0-3.0 (8H, m), 3.63 (3H, s) 3.7-4.3 (1H, m), 5.1-5.9 (2H, m).

EXAMPLE 6 Synthesis of(dl)-(4Z)-7-hydroxy-15-deoxy-16-methyl-11-t-buthyldimethylsilyl-16-trimethylsilyloxy-Δ⁴-^(PGE) 1 methyl ester

An anhydrous ether (10 ml) solution of(dl)-(E)-4-methyl-4-trimethylsilyloxy-1-iodo-1-octene (1.12 g, 3.3 mmol) was cooled to -78° C. and 2.0M t-butyllithium (3.3 ml, 6.6 m mol)was added thereto. The mixture was stirred at -78° C. for 2 hours.Separately, 5 ml of anhydrous ether and then 1.08 g (6.6 m mol) ofhexamethylphosphorous triamide were added to 431 mg (3.3 m mol) of1-pentynylcopper (I) and the mixture was stirred at room temperature for30 minutes to make a homogeneous solution. The solution was then addedto the aforementioned reaction mixture and the resultant mixture wasstirred at -78° C. for 1 hour.

Next, an anhydrous tetrahydrofuran solution (5 ml) of(dl)-4-t-butyldimethylsilyloxy-2-cyclopentenone (616 mg, 3.0 m mol) wasadded to the mixture at -78° C. and stirred at -78° C. for 10 minutesand then at -40° C. for 1 hour. Furthermore, an anhydrous ether solution(5 ml) of methyl (4Z)-6-formyl-4-hexenoate (515 mg, 3.3 m mol) was addedthereto and was stirred at -40° C. for 1 hour.

The reaction mixture was then poured into 2.0 M acetate buffer solutionand 100 ml of hexane was further added thereto and stirred. The wholemixture was filtered through Celite. The filtrate was washed two timeswith an aqueous solution of ammonium chloride containing ammonia, thenwith an aqueous solution of ammonium chloride, and lastly with a salinesolution. The separated organic layer was then dried over anhydrousmagnesium sulfate and concentrated under vacuum to give a crude product.This crude product was subjected to column chromatography on silica gel(hexane: ethyl acetate=9:1) to obtain the desired(dl)-(4Z)-7-hydroxy-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-Δ⁴-PGE₁ methyl ester (1.17 g, 2.0 m mol, yield 67%).

Rf=0.35 (hexane: ethyl acetate=4:1),

¹ H-NMR (δppm in CDCl₃): 0.06 (6H, s), 0.10 (9H, s), 0.90 (12H), 1.16(3H, s), 1.2-1.5 (6H, m), 3.2-3.4 (1H, m), 3.73 (3H, s), 3.7-4.4 (2H,m), 5.15-6.10 (4H, m).

IR (neat): 3500, 3000, 1740, 1255, 1245, 1150, 1110, 1095, 1050, 1000,970, 885, 835, 775, 745 cm⁻¹.

EXAMPLE 7 Synthesis of(dl)-(4Z)-7,8-dehydro-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-Δ⁴-^(PGE) 1 methyl ester

The reaction of(dl)-(4Z)-7-hydroxy-15-deoxy-16-methyl-11-t-butyldimethylsilyloxy-16-trimethylsilyloxy-Δ⁴-PGE₁ methyl ester (1.17 g, 2.0 m mol) obtained in Example 6 withmethanesulfonyl chloride (298 mg, 2.6 m mol) was carried out in thepresence of 4-dimethylaminopyridine (732 mg, 6.0 m mol) according toExample 2. The reaction product was subjected to the same work-up andpurification by column chromatography as Example 2 to provide(dl)-(4Z)-7,8-dehydro-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-Δ⁴-PGE₁ methyl ester (875 g, 1.52 m mol, yield 76%).

Rf=0.55 and 0.50 (hexane: ethyl acetate=4:1).

¹ H-NMR (δppm in CDCl₃): 0.06 (6H, s), 0.09 (9H, s), 0.7-1.0 (12H), 1.12(3H, s), 1.0-1.5 (6H, m), 2.0-3.6 (11H, m), 3.71 (3H, s), 3.9-4.4 (1H,m), 5.1-5.9 (4H, m), 5.9-6.9 (1H, m).

IR (neat): 3020, 1745, 1645, 1245, 1150, 1100, 1060, 1000, 890, 860,835, 775, 750 cm⁻¹.

EXAMPLE 8 Synthesis of(dl)-(4Z)-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-Δ⁴-^(PGE) 1 methy ester

Tetrakis (triphenylphosphine) palladium (0) (52 mg, 0.045 m mol, 3 mol%) was added to(dl)-(4Z)-7,8-dehydro-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethyl-silyloxy-Δ⁴-PGE₁ methyl ester (846 mg, 1.50 m mol), to which tributyltin hydride(4.37 g, 15 m mol) was added with stirring in the atmosphere of nitrogenat room temperature during 3 hours.

Thus resulting reaction mixture was then subjected to columnchromatography on silica gel (firstly hexane only, then hexane:ether=10:1) to give(dl)-(4Z)-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-Δ⁴-PGE₁ methyl ester (610 mg., 1.08 m mol, yield 72%).

Rf=0.40 (hexane: ether=2:1).

¹ H-NMR (δppm in CDCl₃): 0.03 (6H, s), 0.10 (9H, s), 0.87 (12H), 1.17(3H, s), 1.0-1.8 (8H, m), 1.8-3.0 (12H, m), 3.71 (3H, s), 3.8-4.3 (1H,m), 5.1-5.9 (4H, m).

IR (neat): 3000, 1740, 1245, 1150, 1115, 1095, 1000, 970, 860, 835, 775,750 cm⁻¹.

EXAMPLE 9 Synthesis of (dl)-(4Z)-15-deoxy-16-methyl-16-hydroxy-Δ⁴-^(PGE) 1 methyl ester

The(dl)-(4Z)-15-deoxy-16-methyl-11-t-butyldimethylsilyl-16-trimethylsilyloxy-Δ⁴-PGE₁ methyl ester (610 mg, 1.08 m mol) obtained in Example 8 wassubjected to a similar desilylation reaction with the use of hydrogenfluoride-pyridine complex in acetonitrile according to Example 5,followed by the same work-up and purification by column chromatography(hexane: ethyl acetate=1:2), to give(dl)-(4Z)-15-deoxy-16-methyl-16-hydroxy-Δ⁴ -PGE₁ methyl ester (337 mg,0.89 m mol, yield 82%).

Rf=0.20 (hexane: ethyl acetate=1:4),

¹ H-NMR (δppm in CDCl₃): 0.89 (3H, m), 1.17 (3H, s), 1.2-1.8 (8H, m),1.8-3.1 (14H, m), 3.71 (3H, s), 3.8-4.5 (1H, m), 5.2-5.9 (4H, m).

IR (neat): 3400, 3000, 1740, 1160, 1075, 1020, 970, 900, 730 cm⁻¹.

EXAMPLE 10 Synthesis of(dl)-(4Z)-1-nor-1-acetoxymethyl-7-hydroxy-15-deoxy-16-methyl-16-trimethylsilyloxy-Δ⁴-^(PGE) 1 11-t-butyldimethylsilyl ether

An anhydrous ether solution (3 ml) of 510 mg (1.5 m mol) of(dl)-(E)-4-methyl 4-trimethylsilyloxy-1-iodo-1-octene was cooled to -78°C. and 1.5 ml (3 m mol) of 2.0M t-butyllithium was added to the solutionin the atmosphere of nitrogen. The mixture was stirred at -78° C. for 1hour. Then 3 ml of homogeneous anhydrous ether solution of 196 mg (1.5 mmol) of 1-pentynylcopper and 490 mg (3 m mol) of hexamethylphosphoroustriamide was added thereto and the mixture was stirred at -78° C. for 1hour.

Then 2 ml of an anhydrous THF solution of 318 mg (1.5 m mol) of(dl)-4-t-butyldimethylsilyloxy-2-cyclopentenone was added to the mixtureand the resulting mixture was stirred at -78° C. for 30 minutes and at-50° C. for additional 40 minutes.

Thereafter, 3 ml of anhydrous ether solution containing 270 mg (1.6 mmol) of (3Z)-7-acetoxy-3-hexenal was added to the preceding solution andwas stirred for 1 hour.

The reaction was terminated by use of 2.0M acetate buffer solution andthe reaction mixture was extracted with hexane. After having been dried,the organic layer was concentrated and subjected to columnchromatography over silica gel (hexane: ethyl acetate=8:1) to afford 644mg (yield 72%) of the desired(dl)-(4Z)-1-nor-1-acetoxymethyl-7-hydroxy-15-deoxy-16-methyl-16-trimethylsilyloxy-Δ⁴-PGE₁ 11-t-butyldimethyl-silyl ether.

¹ H-NMR (δppm in CDCl₃): 0.06 (6H, s), 0.10 (9H, s), 0.90 (12H), 1.16(3H, s), 1.2-1.5 (6H, m), 2.0 (3H, s), 1.9-3.1 (12H, m), 3.2-3.4 (1H,m), 3.7-4.4 (4H, m), 5.15-6.10 (4H, m).

IR (neat, cm⁻¹): 3500, 3000, 1740, 1250.

EXAMPLE 11 Synthesis of(dl)-(4Z)-1-nor-1-acetoxymethyl-7,8-dehydro-15-deoxy-16-methyl-16-trimethylsilyloxy-Δ⁴-^(PGE) 1-11-t-butyldimethylsilyl ether

In the same way as adopted in Example 7, 540 mg (0.91 m mol) of(dl)-(4Z)-1-nor-1-acetoxymethyl-7-hydroxy-15-deoxy-16-methyl-16-trimethylsilyloxy-Δ⁴-PGE₁ 11-t-butyldimethylsilyl ether dissolved in 5 mol of a methylenechloride was allowed to react with 305 mg (2.5 m mol) of4-dimethylaminopyridine and 91 ml (135 gm, 1.1 m mol) of methanesulfonylchloride. The reaction mixture was subjected to the similar work-up andwas purified by column chromatography to yield 394 mg (yield 75%) of(dl)-(4Z)-1-nor-1-acetoxymethyl-7,8-dehydro-15-deoxy-16-methyl-16-trimethylsilyloxy-Δ⁴-PGE₁ 11-t-butyldimethylsilyl ether.

¹ H-NMR (δppm in CDCl₃): 0.06 (6H, s), 0.09 (9H, s), 0.7-1.0 (12H), 1.12(3H, s), 1.0-1.5 (6H, m), 2.0 (3H, s), 2.0-3.6 (11H, m), 3.9-4.4 (3H,m), 5.1-5.9 (4H, m), 5.9-5.9 (1H, m).

IR (neat, cm⁻¹): 3020, 1745, 1645, 1245.

EXAMPLE 12 Synthesis of(dl)-(4Z)-1-nor-1-acetoxymethyl-15-deoxy-16-methyl-16-trimethylsilyloxy-.DELTA.⁴-^(PGE) 1-11-t-butyldimethylsilyl ether

To a solution of 350 mg (0.61 m mol) of(dl)-(4Z)-1-nor-1-acetoxymethyl-7,8-dehydro-15-deoxy-16-methyl-16-trimethylsilyloxy-Δ⁴-PGE₁ 11-t-butyldimethylsilyl ether obtained in Example 11 in 6 ml ofmethanol, 1 ml of acetic acid was added.

With stirring, 2 g of zinc dust was added to the mixture and theresulting mixture was stirred at room temperature for 5 hours. Thereaction was terminated upon addition of a saturated aqueous solution ofsodium hydrogencarbonate and the reaction mixture was extracted withether. After the organic layer was dried, the solvent was removed byevaporation, and the obtained crude product was subjected to columnchromatography over silica gel to give, 212 mg (yield 60%) of(dl)-(4Z)-1-nor-1-acetoxymethyl-15-deoxy-16-methyl-16-trimethylsilyloxy-.DELTA.⁴-PGE₁ -11-t-butyldimethylsilyl ether.

¹ H-NMR (δppm, CDCl₃): 0.03 (6H, s), 0.10 (9H, s), 0.87 (12H), 1.17 (3H,s), 1.0-1.8 (8H, m), 2.0 (3H, s), 1.8-3.0 (12H, m), 3.8-4.3 (3H, m),5.1-5.9 (4H, m),

IR (neat, cm⁻¹): 3000, 1740, 1245.

EXAMPLE 13 Synthesis of(dl)-(4Z)-1-nor-1-acetoxymethyl-15-deoxy-16-methyl-16-hydroxy-Δ.sup.4-^(-PGE) 1

Two hundred milligrams (0.34 m mol) of(dl)-(4Z)-1-nor-1-acetoxymethyl-15-deoxy-16-methyl-16-trimethyl-silyloxy-.DELTA.⁴-PGE₁ 11-butyldimethylsilyl ether obtained in Example 12 was subjectedto the desilylation reaction with the use of hydrogen fluoride-pyridinecomplex in acetonitrile according to Example 9, followed by the similarwork-up and purification by column chromatography (hexane: ethylacetate=1:2) to give 109 mg (yield 81%) of(dl)-(4Z)-1-nor-1-acetoxymethyl-15-deoxy-16-methyl-16-hydroxy-Δ.sup.4-PGE₁.

¹ H-NMR (δppm, CDCl₃): 0.90 (3H, m), 1.17 (3H, s), 1.2-1.8 (8H, m), 2.0(3H, s), 1.8-3.1 (14H, m), 3.8-4.5 (3H, m), 5.2-5.9 (4H, m),

IR (neat, cm⁻¹): 3400, 300, 1740.

INDUSTRIAL APPLICATIONS

A new process of this invention has made it possible to advantageouslyproduce 16-substituted prostaglandin Es, which are useful as a medicinehaving an anti-ulcer activity, on an industrial scale. Also7-hydroxy-16-substituted prostaglandin Es and 16-substituted Δ⁷-prostaglandin Es, which are formed as the synthetic intermediates inthe aforementioned process, are per se useful compounds as medicine.

What we claim is:
 1. A process for producing 16-substitutedprostaglandin Es, which include compounds expressed by the followingformula (I), or their enantiomers, or their mixtures of arbitrary mixingratio, ##STR14## wherein R¹ indicates COOR², CH₂ OR³, in which R²indicates a hydrogen atom, a substituted or unsubstituted C₁ -C₁₀ alkylgroup, a substituted or unsubstituted C₃ -C₁₀ cycloalkyl group, or asubstituted or unsubstituted phenyl group, and R³ indicates a hydrogenatom, a tri(C₁ -C₇) hydrocarbon silyl group, a group which forms anacetal bond together with the oxygen atom of a hydroxyl group, or a C₂-C₇ aryl group: R⁴ and R⁵ are identical or different, each representinga hydrogen atom, a tri(C₁ -C₇) hydrocarbon silyl group, or a group whichforms an acetal bond together with the oxygen atom of a hydroxyl group;R⁶ indicates a hydrogen atom, a C₁ -C₄ alkyl group, or vinyl group; R⁷indicates a linear or branched C₃ -C₈ alkyl group, an alkenyl group, oran alkynyl group, which may contain an oxygen atom; a phenyl group, aphenoxy group, or a C₃ - C₁₀ cycloalkyl group, which may be substituted;or a linear or branched C₁ -C₅ alkyl group which is substituted by a C₁-C₆ alkoxy group, a phenyl group, a phenoxy group, or a C₃ -C₁₀cycloalkyl group, which may be substituted; and Y indicates CH₂ X orXCH₂, in which X represents an ethylene group, a cis- or trans-vinylenegroup, or an ethynylene group,which process comprises selectivelyreducing using an organic tin hydride compound and a zerovalentpalladium catalyst the double bonds at the 7- and 8-positions of16-substituted Δ⁷ -prostaglandin Es, which include compounds expressedby the following formula (II), their enantiomers, or their mixtures ofarbitrary mixing ratio, further followed by the deprotecting reactionand/or the hydrolytic reaction, if necessary, ##STR15## wherein R¹, R⁴,R⁵, R⁶, R⁷, and Y are as defined hereinabove.